1. Field of the Invention
The present invention relates to non-effervescent, orally disintegrating pharmaceutical dosage forms suitable for administering free base clozapine to a subject in need thereof, and methods of making and using the same.
2. Related Art
Clozapine, an atypical antipsychotic agent, is commonly prescribed for the management and symptomatic relief from the symptoms of severe schizophrenia. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors, and can also be used for treating various dopamine-mediated behaviors. However, due to the risk of side effects that include agranulocytosis, hyperglycemia, hypertriglyceridemia, and increased appetite, patients are typically only prescribed clozapine after more conventional treatments (e.g., chlorpromazine or haloperidol) have proven inadequate.
Clozapine is presently available in oral tablet and orally disintegrating tablet dosage forms (e.g., FAZACLO® 25, 50 and 100 mg orally disintegrating tablets, Alamo Pharmaceuticals, LLC, Beverly Hills, Calif.). Orally disintegrating tablets can be preferred for dosage forms for patients suffering from schizophrenia because they can be taken without water intake and disintegrate immediately upon contacting the tongue or buccal cavity, thereby improving patient compliance.
However, during clinical trials patients have complained of a bitter taste when administered orally disintegrating tablets containing clozapine. While the free base form of clozapine is tasteless, the acid addition salt of clozapine is bitter tasting. An acid contained within an effervescent orally disintegrating tablet can react with free base clozapine during storage, thereby exacerbating its bitter taste. Thus, effervescent clozapine orally disintegrating dosage forms (that contain an acid as part of an effervescent couple) typically include a protective polymer coating surrounding the free base clozapine granules (see, e.g., U.S. Pat. Nos. 5,178,878 and 6,024,981). The need to apply a polymer coating to free base clozapine granules adds unwanted cost and time to the manufacturing process. Moreover, the fragility of a polymer coating around the free base clozapine granules requires that limited compression force be used during tableting to avoid damaging the polymer coating, and thereby adding challenges into product handling and packaging.